Trifluoromethyl Sulfoxides: Reagents for Metal‐Free C−H Trifluoromethylthiolation

Abstract

Trifluoromethyl sulfoxides are a new class of trifluoromethylthiolating reagent. The sulfoxides engage in metal‐free C−H trifluoromethylthiolation with a range of (hetero)arenes. The method is also applicable to the functionalization of important compound classes, such as ligand derivatives and polyaromatics, and in the late‐stage trifluoromethylthiolation of medicines and agrochemicals. The isolation and characterization of a sulfonium salt intermediate supports an interrupted Pummerer reaction mechanism.

Synthesis of 3-SCF2H-/3-SCF3-chromones via Interrupted Pummerer Reaction/Intramolecular Cyclization Mediated by Difluoromethyl or Trifluoromethyl Sulfoxide and Tf2O

“…Based on the above experimental results and previous reports, − a plausible mechanistic pathway for this reaction was postulated (Scheme ). First, the reactive electrophilic intermediate I , rather than the previously presumed analogous CHF 2 SOTf and BnOTf, , was generated from the reaction of difluoromethyl sulfoxide and Tf 2 O.…”

“…In the pioneering work of the Procter group, bench-stable trifluoromethyl sulfoxide has been synthesized and used as a trifluoromethylthiolating reagent for installing the SCF 3 group onto nucleophilic (hetero)arenes through an interrupted Pummerer reaction (Scheme 1a). 22 In our recent work, we also realized the synthesis of a series of 4-(trifluoromethylthio)isocoumarins from the reactions of 2alkynylbenzoates with trifluoromethylthiolating reagent via an intramolecular trifluoromethylthiolation and lactonization (Scheme 1b). 23 Inspired by these advances, we were interested in investigating whether benzyl difluoromethyl sulfoxide (BnS(O)CF 2 H) 1j (Figure 2) could be used as a new difluoromethylthiolating reagent to realize the analogous difluoromethylthiolation in organic synthesis.…”

“…Given that sulfoxides have been verified to be versatile sulfur reagents in organic synthesis, − we conceived whether sulfoxide containing CF 2 H can be developed as a powerful difluoromethylthiolating agent for the construction of SCF 2 H substituted products. In the pioneering work of the Procter group, bench-stable trifluoromethyl sulfoxide has been synthesized and used as a trifluoromethylthiolating reagent for installing the SCF 3 group onto nucleophilic (hetero)­arenes through an interrupted Pummerer reaction (Scheme a) . In our recent work, we also realized the synthesis of a series of 4-(trifluoromethylthio)­isocoumarins from the reactions of 2-alkynylbenzoates with trifluoromethylthiolating reagent via an intramolecular trifluoromethylthiolation and lactonization (Scheme b) .…”

Late-stage C–H thiolation via sulfonium salts using β-sulfinylesters as the versatile sulfur source

“…In addition, the selective cleavage of one of the three C-S bonds of aryl sulfonium salts via nucleophilic substitution were also realized to give aryl sul des (Scheme 1b). [36][37][38][39][40][41][42][43][44] While this strategy is promising, alkenyl, alkynyl, and alkyl sulfonium salts were not tolerated due to the fact that both of alkenyl and alkynyl sulfonium salts are good electrophilic Michael acceptors, [45][46][47][48][49] and alkenyl C(sp 2 )-S, C(sp)-S, and C(sp 3 )-S bonds of sulfonium salts are more prone to be attacked by nucleophiles than aryl C(sp 2 )-S bond. 36,50,51 Undoubtedly, the development of a general, practical, and TM-free C-H thiolation reaction for the construction of functionalized sul des, including aryl, alkenyl, alkynyl, and alkyl sul des, is highly desirable.…”

Generation of non-stabilized alkyl radicals from thianthrenium salts for C–B and C–C bond formation

“…In general, the reactivity of sulfonium salts is determined by the positive charge that they contain, which is mainly located at the sulfur atom. In this context, many sulfonium salt-based reagents including Umemoto's reagent have been designed for electrophilic substitution [4][5][6][7][8][9][10] . In nature, enzymes catalyzing the generation of alkyl radicals from sulfonium salts known to date all belong to the radical S-adenosylmethionine (SAM) superfamily (Fig.…”